This application addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge Topic, 03-HL-101: Identify and Validate Clinically Relevant, Quantifiable Biomarkers of Diagnostic and Therapeutic Responses to Blood, Vascular, Cardiac, and Respiratory Tract Dysfunction. Each year 1.4 million individuals have an acute coronary syndrome (ACS). Their prognosis is highly variable and therapeutic options broad. Circulating biomarkers of necrosis such as troponin have proven invaluable in aiding not only with diagnosis but also prognosis. However, limitations to the analytical performance of current assays at very low concentrations have constrained our ability to risk stratify a substantial number of patients. New, ultrasensitive troponin assays are being developed that have far greater precision at very low concentrations. Our group has led initial studies with these assays, which are 1-2 orders of magnitude more sensitive than current commercial assays, and found that they allow for the identification of myocardial ischemia earlier and in more patients than conventional assays do. In addition to cardiomyocyte-derived proteins released during myocardial injury, there is also growing interest in circulating biomarkers that reliably reflect other relevant pathobiologies central to ACS including inflammation, thrombosis, and ventricular wall stress. Moreover, recent advances in metabolic profiling technologies have enabled the monitoring of hundreds of metabolites ("metabolomics"), that may be deranged very early in disease states. We believe the combination of an ultrasensitive assay for a cardiomyocyte-specific structural protein plus proteins and metabolite markers from relevant pathobiological pathways offers the best chance to develop a comprehensive biomarker panel that offers significant advances in risk assessment. Moreover, such biomarkers hold the promise of enabling clinicians to tailor therapy so as to minimize morbidity and mortality. Thus, the overall goal of this proposal is to validate the ability of state-of-the-art biomarkers to predict major adverse cardiovascular outcomes and benefit of therapy in ACS. To achieve this goal, we will leverage the strength of our TIMI Study Group clinical trials, which offer (1) large numbers of carefully phenotyped patients and adjudicated clinical outcomes, (2) a wealth of additional data including Holter monitoring for ischemia, angiograms, and multiple traditional biomarkers, and (3) randomized allocation to specific pharmacotherapies. In Aim 1, we will investigate the prognostic significance of ultrasensitive troponin measurements for adverse cardiovascular outcomes (a) at the time of presentation, (b) after clinical stabilization, and (c) following percutaneous coronary intervention (PCI). In Aim 2 we will investigate the prognostic significance of novel circulating protein and metabolic biomarkers. In Aim 3 we will test the association between levels of novel biomarkers and the benefit of specific pharmacotherapies. Public Health Relevance: The prognosis in patients suffering a heart attack is highly variable and the therapeutic options broad. We believe extremely sensitive blood tests for damage to heart muscle plus other novel blood tests for inflammation, heart muscle stress, and clotting offer the potential to improve a clinician's ability to determine a patient's prognosis and to tailor therapy so as to minimize the complications of a heart attack.